Triple Therapy for Bladder Cancer

(RESOLVE Trial)

Overseen by Sumati V Gupta

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: University of Utah

Must not be taking: Valproic acid, Immunosuppressants

Disqualifiers: Gilbert syndrome, Active malignancy, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial tests a combination of two drugs, durvalumab and belinostat, for treating advanced urothelial cancer. It targets patients whose cancer has spread or cannot be surgically removed. Durvalumab helps the immune system attack cancer, and belinostat stops proteins that help cancer cells grow.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, there is a requirement for a washout period (time without taking certain medications) of at least 5 half-lives for prohibited medications before starting the trial treatment.

How is the triple therapy for bladder cancer unique?

The triple therapy for bladder cancer combines Belinostat, Durvalumab, and Tremelimumab, which is unique because it uses a combination of drugs that target different pathways in the immune system to fight cancer. Durvalumab and Tremelimumab are immune checkpoint inhibitors that help the immune system recognize and attack cancer cells, while Belinostat is a histone deacetylase inhibitor that can modify gene expression to stop cancer cell growth. ^{1 2 3 4 5}

Research Team

Sumati V Gupta

Principal Investigator

Huntsman Cancer Institute/ University of Utah

Eligibility Criteria

Adults (18+) with advanced urothelial carcinoma that's spread or can't be surgically removed, who've tried at least one therapy or declined/aren't suitable for standard treatments. They must have ARID1A gene alterations, measurable disease, good organ function and blood counts, and a life expectancy of over 12 weeks. Women must not be pregnant and use effective contraception.

Inclusion Criteria

My cancer can be measured by scans.

I have recovered from previous treatment side effects, or they are minor and stable.

My kidneys are working well enough, with a creatinine clearance of at least 30 mL/min.

Exclusion Criteria

I have brain metastases or cranial epidural disease.

I have been treated with durvalumab and tremelimumab before.

I haven't had cancer treatment or experimental therapy in the last 14 days or within 5 half-lives of the drug.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive durvalumab and tremelimumab initially, followed by belinostat starting from cycle 2. Treatment repeats every 21 days for 7 cycles, then durvalumab every 28 days for up to 24 cycles.

Up to 24 cycles

Visits every 21 days for 7 cycles, then every 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

3 years

Every 3 months for 1 year, then every 6 months for 2 years

Treatment Details

Interventions

• Belinostat (Histone Deacetylase Inhibitor)
• Durvalumab (Monoclonal Antibodies)
• Tremelimumab (Monoclonal Antibodies)

Trial Overview The trial is testing the combination of two drugs: Belinostat (an HDAC inhibitor that may stop cancer cells from growing) and Durvalumab (a monoclonal antibody designed to help the immune system attack cancer). It aims to find the safest dose with acceptable side effects for patients with specific genetic changes in their tumors.

Participant Groups

Group I: Treatment (durvalumab, belinostat) Experimental Treatment 2 Interventions

Phased Doublet Therapy Eligible patients enrolled will be administered durvalumab 1120 mg every 3 weeks C1 through C7 followed by durvalumab 1500 mg every four weeks C8 through C15 (T300+D). Belinostat administration will begin with Cycle 2 for 6 cycles. From cycle 8 on, durvalumab will be administered in 28-day cycles to complete up to a total of 15 cycles of treatment or until treatment discontinuation criteria is met. Belinostat will be administered at the assigned dose level on days one through five of every applicable cycle. Belinostat administration on five consecutive days is preferred. Administration within seven days of Day 1 is allowed as needed to accommodate holidays and infusion schedules. Durvalumab will be infused over 60 minutes (±10 minutes). For Cycles 2-7, belinostat will be infused over 30 minutes (-5 minutes/+15 minutes) and will be administered after durvalumab. Separate infusion bags and filters must be used for each infusion.

Who Is Running the Clinical Trial?

University of Utah

Lead Sponsor

Trials

1,169

Recruited

1,623,000+

Jeffrey Wilkins

University of Utah

Chief Medical Officer since 2022

MD from Meharry Medical College

Stephen Tullman

University of Utah

Chief Executive Officer since 2022

BS in Accounting from Rutgers University

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

In a phase 3 trial involving 1032 patients with metastatic urothelial carcinoma, durvalumab alone showed a median overall survival of 14.4 months in patients with high PD-L1 expression, compared to 12.1 months with standard chemotherapy, although this difference was not statistically significant.

The combination of durvalumab and tremelimumab resulted in a median overall survival of 15.1 months in the overall patient population, compared to 12.1 months for chemotherapy, but again, this did not meet the primary endpoint for significance, highlighting the need for further research into which patients may benefit from these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Powles, T., van der Heijden, MS., Castellano, D., et al.[2021]

The combination of nivolumab, an immune checkpoint inhibitor, with neoadjuvant chemotherapy (NAC) is being investigated in a Phase III trial (ENERGIZE) for its efficacy in treating muscle-invasive bladder cancer (MIBC) in cisplatin-eligible patients, potentially improving overall survival rates.

Linrodostat mesylate, an IDO1 inhibitor, shows promise when combined with nivolumab, as it has demonstrated safety and preliminary clinical activity in metastatic urothelial carcinoma, suggesting a synergistic effect that could enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ENERGIZE: a Phase III study of neoadjuvant chemotherapy alone or with nivolumab with/without linrodostat mesylate for muscle-invasive bladder cancer. Sonpavde, G., Necchi, A., Gupta, S., et al.[2020]

Neoadjuvant immunotherapy using immune checkpoint inhibitors (ICIs) like anti-PD-(L)1 and anti-CTLA-4 antibodies shows promising efficacy in localized muscle-invasive bladder cancer, with pathological complete response rates between 31% and 46%.

The safety profile of these treatments is generally acceptable, with severe adverse events reported in 6% to 41% of patients, indicating that while there are risks, the potential benefits warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant Immunotherapy for Muscle-Invasive Bladder Cancer. Peyrottes, A., Ouzaid, I., Califano, G., et al.[2021]

Neoadjuvant immune checkpoint inhibitors (ICI) and antibody-drug conjugates like enfortumab vedotin show promising safety and potential for achieving pathologic complete response (pCR) in patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy, based on recent clinical trials.

Combining ICIs with radiation therapy appears to be safe and effective, highlighting the need for biomarkers to tailor treatment options and improve outcomes for individual patients with MIBC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Muscle invasive bladder cancer: where is the field headed? Ghatalia, P., Kaur, J., Sonpavde, G.[2023]

In a phase 1 study involving 8 patients with localized muscle invasive bladder cancer, the combination of atezolizumab, radiation therapy, and gemcitabine resulted in significant gastrointestinal toxicity, leading to dose adjustments and the study's termination.

Despite the serious side effects observed, no grade 4 or 5 adverse effects were reported, indicating that while the treatment combination is concerning in terms of safety, it did not lead to the most severe complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 Trial of Atezolizumab Plus Trimodal Therapy in Patients With Localized Muscle-Invasive Bladder Cancer. Marcq, G., Souhami, L., Cury, FL., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. [2021]

2. England pubmed.ncbi.nlm.nih.gov

ENERGIZE: a Phase III study of neoadjuvant chemotherapy alone or with nivolumab with/without linrodostat mesylate for muscle-invasive bladder cancer. [2020]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Neoadjuvant Immunotherapy for Muscle-Invasive Bladder Cancer. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Muscle invasive bladder cancer: where is the field headed? [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Phase 1 Trial of Atezolizumab Plus Trimodal Therapy in Patients With Localized Muscle-Invasive Bladder Cancer. [2021]